Comparative Toll-Like Receptor 4-Mediated Innate Host Defense to Bordetella Infection

Pathobiology Graduate Program, Immunology Research Laboratories, Department of Veterinary Science, The Pennsylvania State University, University Park, PA 16802, USA.
Infection and Immunity (Impact Factor: 3.73). 01/2006; 73(12):8144-52. DOI: 10.1128/IAI.73.12.8144-8152.2005
Source: PubMed


Bordetella pertussis, B. parapertussis, and B. bronchiseptica are closely related species associated with respiratory disease in humans and other mammals. While B. bronchiseptica has a wide host range, B. pertussis and B. parapertussis evolved separately from a B. bronchiseptica-like progenitor to naturally infect only humans. Despite very different doubling times in vitro, all three establish similar
levels of infection in the mouse lung within 72 h. Recent work has revealed separate roles for Toll-like receptor 4 (TLR4)
in immunity to B. pertussis and B. bronchiseptica, while no role for TLR4 during B. parapertussis infection has been described. Here we compared the requirement for TLR4 in innate host defense to these organisms using the
same mouse infection model. While B. bronchiseptica causes lethal disease in TLR4-deficient mice, B. pertussis and B. parapertussis do not. Correspondingly, TLR4 is critical in limiting B. bronchiseptica but not B. pertussis or B. parapertussis bacterial numbers during the first 72 h. Interestingly, B. bronchiseptica induces a TLR4-dependent cytokine response that is considerably larger than that induced by B. pertussis or B. parapertussis. Analysis of their endotoxins using RAW cells suggests that B. bronchiseptica lipopolysaccharide (LPS) is 10- and 100-fold more stimulatory than B. pertussis or B. parapertussis LPS, respectively. The difference in LPS stimulus is more pronounced when using HEK293 cells expressing human TLR4. Thus,
it appears that in adapting to infect humans, B. pertussis and B. parapertussis independently modified their LPS to reduce TLR4-mediated responses, which may compensate for slower growth rates and facilitate
host colonization.

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    • "It was shown that TLR4-deficient C3H/HeJ mice had a more severe course of B. 129 pertussis infection when compared with TLR4-sufficient C3H/HeN mice (Mann et al., 2005, 130 Higgins et al., 2006, Banus et al., 2008). TLR4 expressed by DCs and macrophages plays a 131 central role in protective immunity to this pathogen. "
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    • "As lack of TLR4 signaling may lead to impaired immune responses, evasion of TLR4 may correspond with its intense virulence when transmitting between humans as a respiratory pathogen and its reduced virulence when transmitted by ectothermic insect vectors [20], [21]. Similarly Bordetella pertussis, and B. parapertussis, which are weak agonists of human TLR4 compared with B. bronchiseptica [22], [23] cause more severe disease within their hosts and are among the most contagious pathogens circulating in the human population [24]. "
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    • "The difference in the number of PMN induced by B. bronchiseptica LPS and B. bronchiseptica bacteria could be explained by selective activation induced by the LPS of the PMN through its PAMP recognition receptors, more specifically through TLR4. Mann et al. [51, 54, 55] and Kirimanjeswara [56] documented TLR4 activation by B. bronchiseptica LPS and they noted its importance for PMN recruitment and cytokine production. "
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